Acetazolamide sodium (ACZ.Na) powder is a parenteral dosage form of acetazolamide, which is a carbonic anhydrase inhibitor and used to lower the intraocular pressure. Thus, the acetazolamide sodium is mainly used for treating glaucoma. Other indications include epilepsy, congestive heart failure, drug-induced edema, and mountain sickness. In some reports, the acetazolamide (ACZ) is present in two crystal structures, such as triclinic and monoclinic. The triclinic structure is commercially available due to the thermodynamic stable at 20° C. Generally, the acetazolamide is granulated into tablet and administered through oral route. Since the acetazolamide has an extremely low solubility in water, the bioavailability of acetazolamide tablet is regarded as an issue. However, the acetazolamide sodium shows a different characteristic on solubility. The acetazolamide sodium powder easily dissolves in water so as to be reconstituted as injectable dosage form. Therefore, the acetazolamide sodium has much higher bioavailability than acetazolamide.
In the commercial acetazolamide sodium powder, i.e., acetazolamide for injection, it is obtained from lyophilizing 10% (w/v) solution of acetazolamide sodium. The lyophilizing process includes freezing a constituted solution (freezing stage), sublimating ice (primary drying stage), and removing solvent (secondary drying stage). In the freezing stage, the temperature of solution is adjusted below the eutectic temperature of solution. After the freezing stage, the pressure of drying chamber is reduced to a value required for sublimating water and meanwhile a significant heat is supplied as the latent heat for sublimating water. In the final stage, the pressure is further reduced and the temperature is slightly increased to remove the bound water, which is about 10-35% of total water contents. In the view of the whole process, lyophilization costs more due to the needs of refrigeration, vacuum, and long cycle times. As a result, lyophilization costs about 5-10 times higher than spray drying, which is generally adopted in chemical industry but rarely used in manufacturing a pharmaceutical powder for injection.
Spray drying is one of the conventional techniques in chemical industry since 1920s and has several advantages in comparison with the lyophilization. For example, the spray drying can save more than 50% energy than the lyophilization. In general, the spray drying primarily includes three stages. Firstly, a concentrated solution is atomized into numerous liquid droplets. Then, the liquid droplets contact the heated gas, e.g., air or nitrogen (N2), and then the liquid droplets evaporate to accompany with the nucleation of particles in a short period (such as about a few seconds). Finally, the dried particles are collected by a cyclone system incorporated with a bag filter or wet scrubber. In view of the industrial process, the advantages for spray drying include the continuous mass production, automated controlling, higher energy efficiency, and feasible applications of both heat-resistant and heat-sensitive materials. Therefore, spray dryers are widely applied in various industries. However, it is rarely applied for manufacturing active pharmaceutical ingredients (APIs) in pharmaceutical industry. In the reported literatures, there are some disclosures related to spray drying of acetazolamide, but that of acetazolamide sodium has not been disclosed yet. The follows are some prior arts related to spray drying acetazolamide.
US2006/0024374 discloses a process for preparing solid lipid nanoparticles (SLNs), which includes 0.1% to 7.0% of a pharmacologically active substance. Acetazolamide was disclosed as one of the pharmacologically active substances. In the disclosed process, the SLNs dispersion is prepared by microemulsion, precipitation, and washing. Then the resultant SLNs dispersion is dried by lyophilization, spray drying, or evaporation to obtain the SLNs with the drug incorporated.
US2007/0020336 discloses an ophthalmic composition, which is an aqueous suspension comprising an active pharmaceutical ingredient (API), cyclodextrin, and water.
One of the disclosed APIs is acetazolamide. Moreover, the ophthalmic composition powder can be obtained by lyophilizing or spray drying the disclosed aqueous suspension.
US2008/0311162 discloses a compacting method of making a solid composition comprising at least one film enrobing a compacted fill material having a pressure sensitive multiparticulate and/or a cushioning agent. Among the disclosed pressure sensitive multiparticulates, acetazolamide is one of the candidates and can be prepared by granulation, spray drying, lyophilization, and the like. However, no more details about the spray drying are reported.
US2009/0098200 discloses a solid composition comprising at least one lipophilic active compound and two or more polymers. It is disclosed that acetazolamide is one of diuretics as the lipophilic active compound. Moreover, the composition can be prepared by a method comprising the steps of (i) providing a clear and homogeneous solution of at least one lipophilic active compound and two or more polymers in a mixture of water and an organic solvent; and (ii) spray drying the constituted solution of (i) to form a dry powder.
US2013/0059795 discloses a drying method for preparing a composition comprising a leaf protein-lipid-soluble material complex, in which the lipid-soluble materials includes acetazolamide and other drug substances. According to the disclosed technique, a suspension of leaf protein in water is constructed and then mixed with the solution of lipid-soluble material in organic solvent. After mixing, the mixture is dried by freezing-drying, precipitation, or spray drying to form the leaf protein-lipid-soluble material complex powder.
U.S. Pat. No. 8,216,495 discloses a spray drying method for preparing a solid dispersion comprising polyvinyl alcohol-polyethylene glycol graft copolymer and biopharmaceutical classification system (BCS) class II or IV drug. The copolymer is dissolved in a water/first alcohol mixture. Then, the drug is dissolved in a mixture of a second alcohol and non-alcoholic organic solvent. Subsequently, the constituted solutions are mixed and then spray dried to produce the solid dispersion.
The above spray drying methods are mainly utilized for preparing solid composition comprising acetazolamide and at least one excipient, such as lipid, cyclodextrin, protein, and polymer. In order to prepare the composite material, US2007/0020336 discloses an aqueous suspension system in the spray drying process because of the limitation of extremely low solubility of acetazolamide in water. Although the ophthalmic composition powder can be prepared, the particle size and crystal structure of acetazolamide will be invariable by such a spray drying method. On the other hand, various conventional methods utilize the organic solvent to overcome the demerit of solubility. However, the organic solvent will evolve another drawback, i.e., the residual solvent, which is harmful to human body.
Among the above spray drying methods for preparing acetazolamide, the hydrolysis reaction of acetazolamide does not occur in the process because of the application of organic solvent or insoluble acetazolamide in water. However, hydrolysis is a considerable attribute in the process of manufacturing acetazolamide sodium. As a result, lyophilization is applied to manufacturing the commercial product of acetazolamide for inejction.
Hence, this invention provides a spray drying method for preparing acetazolamide sodium powder as the acetazolamide for injection to replace the commercialized technique, i.e., lyophilization. Accordingly, the present invention provides a method for preparing acetazolamide sodium powder that can be formulated as acetazolamide for injection and reconstituted for intravenous administration by spray drying.